Publications by authors named "Rebecca Mills"

35 Publications

Toward Replacing Late Gadolinium Enhancement With Artificial Intelligence Virtual Native Enhancement for Gadolinium-Free Cardiovascular Magnetic Resonance Tissue Characterization in Hypertrophic Cardiomyopathy.

Circulation 2021 Aug 7;144(8):589-599. Epub 2021 Jul 7.

Oxford Centre for Clinical Magnetic Resonance Research, Oxford Biomedical Research Centre National Institute for Health Research, Division of Cardiovascular (Q.Z., M.J.B., E.L., M.Shanmuganathan, I.A.P., C.N., R.M., K.W., E.H., A.B., S.D.P., H.C.W., S.N., V.M.F., S.K.P.).

Background: Late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) imaging is the gold standard for noninvasive myocardial tissue characterization but requires intravenous contrast agent administration. It is highly desired to develop a contrast agent-free technology to replace LGE for faster and cheaper CMR scans.

Methods: A CMR virtual native enhancement (VNE) imaging technology was developed using artificial intelligence. The deep learning model for generating VNE uses multiple streams of convolutional neural networks to exploit and enhance the existing signals in native T1 maps (pixel-wise maps of tissue T1 relaxation times) and cine imaging of cardiac structure and function, presenting them as LGE-equivalent images. The VNE generator was trained using generative adversarial networks. This technology was first developed on CMR datasets from the multicenter Hypertrophic Cardiomyopathy Registry, using hypertrophic cardiomyopathy as an exemplar. The datasets were randomized into 2 independent groups for deep learning training and testing. The test data of VNE and LGE were scored and contoured by experienced human operators to assess image quality, visuospatial agreement, and myocardial lesion burden quantification. Image quality was compared using a nonparametric Wilcoxon test. Intra- and interobserver agreement was analyzed using intraclass correlation coefficients (ICC). Lesion quantification by VNE and LGE were compared using linear regression and ICC.

Results: A total of 1348 hypertrophic cardiomyopathy patients provided 4093 triplets of matched T1 maps, cines, and LGE datasets. After randomization and data quality control, 2695 datasets were used for VNE method development and 345 were used for independent testing. VNE had significantly better image quality than LGE, as assessed by 4 operators (n=345 datasets; <0.001 [Wilcoxon test]). VNE revealed lesions characteristic of hypertrophic cardiomyopathy in high visuospatial agreement with LGE. In 121 patients (n=326 datasets), VNE correlated with LGE in detecting and quantifying both hyperintensity myocardial lesions (=0.77-0.79; ICC=0.77-0.87; <0.001) and intermediate-intensity lesions (=0.70-0.76; ICC=0.82-0.85; <0.001). The native CMR images (cine plus T1 map) required for VNE can be acquired within 15 minutes and producing a VNE image takes less than 1 second.

Conclusions: VNE is a new CMR technology that resembles conventional LGE but without the need for contrast administration. VNE achieved high agreement with LGE in the distribution and quantification of lesions, with significantly better image quality.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.054432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8378544PMC
August 2021

Medium-term effects of SARS-CoV-2 infection on multiple vital organs, exercise capacity, cognition, quality of life and mental health, post-hospital discharge.

EClinicalMedicine 2021 Jan 7;31:100683. Epub 2021 Jan 7.

Nuffield Department of Medicine, NIHR Oxford BRC, University of Oxford, Oxford, United Kingdom.

Background: The medium-term effects of Coronavirus disease (COVID-19) on organ health, exercise capacity, cognition, quality of life and mental health are poorly understood.

Methods: Fifty-eight COVID-19 patients post-hospital discharge and 30 age, sex, body mass index comorbidity-matched controls were enrolled for multiorgan (brain, lungs, heart, liver and kidneys) magnetic resonance imaging (MRI), spirometry, six-minute walk test, cardiopulmonary exercise test (CPET), quality of life, cognitive and mental health assessments.

Findings: At 2-3 months from disease-onset, 64% of patients experienced breathlessness and 55% reported fatigue. On MRI, abnormalities were seen in lungs (60%), heart (26%), liver (10%) and kidneys (29%). Patients exhibited changes in the thalamus, posterior thalamic radiations and sagittal stratum on brain MRI and demonstrated impaired cognitive performance, specifically in the executive and visuospatial domains. Exercise tolerance (maximal oxygen consumption and ventilatory efficiency on CPET) and six-minute walk distance were significantly reduced. The extent of extra-pulmonary MRI abnormalities and exercise intolerance correlated with serum markers of inflammation and acute illness severity. Patients had a higher burden of self-reported symptoms of depression and experienced significant impairment in all domains of quality of life compared to controls (<0.0001 to 0.044).

Interpretation: A significant proportion of patients discharged from hospital reported symptoms of breathlessness, fatigue, depression and had limited exercise capacity. Persistent lung and extra-pulmonary organ MRI findings are common in patients and linked to inflammation and severity of acute illness.

Funding: NIHR Oxford and Oxford Health Biomedical Research Centres, British Heart Foundation Centre for Research Excellence, UKRI, Wellcome Trust, British Heart Foundation.
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http://dx.doi.org/10.1016/j.eclinm.2020.100683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808914PMC
January 2021

Crazy-Paving: A Computed Tomographic Finding of Coronavirus Disease 2019.

Clin Pract Cases Emerg Med 2020 Aug;4(3):461-463

Jefferson Health - Northeast, Department of Critical Care, Philadelphia, Pennsylvania.

Introduction: Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2. COVID-19 first occurred in Wuhan, China, in December 2019, and by March 2020 COVID-19 was declared a global pandemic.

Case Presentation: We describe a case of a 52-year-old female with past medical history of asthma, type 2 diabetes, and previous tobacco use who presented to the emergency department with dyspnea and was found to be positive for COVID-19. We discuss the computed tomographic finding of "crazy-paving" pattern in the patient's lungs and the significance of this finding in COVID-19 patients.

Discussion: Emergency providers need to be aware of the different imaging characteristics of various stages of COVID-19 to appropriately treat, isolate, and determine disposition of COVID-19 infected patients. Ground-glass opacities are the earliest and most common imaging finding for COVID-19. Crazy-paving pattern is defined as thickened interlobular septa and intralobular lines superimposed on diffuse ground-glass opacities and should be recognized by emergency providers as a radiographic finding of progressive COVID-19.
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http://dx.doi.org/10.5811/cpcem.2020.5.47998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434282PMC
August 2020

CSA-90 reduces periprosthetic joint infection in a novel rat model challenged with local and systemic Staphylococcus aureus.

J Orthop Res 2020 09 11;38(9):2065-2073. Epub 2020 Feb 11.

Department of Orthopaedic Research and Biotechnology, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.

Infection of orthopedic implants is a growing clinical challenge to manage due to the proliferation of drug-resistant bacterial strains. In this study, we aimed to investigate whether the treatment of implants with ceragenin-90 (CSA-90), a synthetic compound based on endogenous antibacterial peptides, could prevent infection in a novel rat model of periprosthetic joint infection (PJI) challenged with either local or systemic Staphylococcus aureus. A novel preclinical model of PJI was created using press-fit porous titanium implants in the distal femur of male Wistar rats. Sterile implants were pre-treated with 500 μg CSA-90 in saline. S. aureus was applied either directly at the time of surgery or administered via tail vein injection immediately afterward. Animals were monitored daily for clinical and radiographic evidence of infection for a total of 6 weeks. Post-study microbiological, radiographic, and histological analysis were performed to determine the incidence of PJI and assess osseointegration. CSA-90 treated groups demonstrated a reduced rate of PJI as confirmed by deep tissue swab culture at the time of cull compared with untreated groups with both local (33% vs 100%; P = .009) and systemic (10% vs 90%; P < .0001) S. aureus inoculation. Median survival time also increased from 8 to 17 days and from 8 to 42 days, respectively. In conclusion, this study describes a novel preclinical model of local and hematogenous PJI using a porous metal implant. CSA-90 reduced the incidence of PJI in this model supporting its further development as an antimicrobial coating for orthopedic implants.
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http://dx.doi.org/10.1002/jor.24618DOI Listing
September 2020

The application of ceragenins to orthopedic surgery and medicine.

J Orthop Res 2020 09 10;38(9):1883-1894. Epub 2020 Feb 10.

Orthopaedic Research & Biotechnology Unit, The Children's Hospital at Westmead, Sydney, NSW, Australia.

Osteomyelitis and infections associated with orthopedic implants represent a significant burden of disease worldwide. Ceragenins (CSAs) are a relatively new class of small-molecule antimicrobials that target a broad range of Gram-positive and Gram-negative bacteria as well as fungi, viruses, and parasites. This review sets the context of the need for new antimicrobial strategies by cataloging the common pathogens associated with orthopedic infection and highlighting the increasing challenges of managing antibiotic-resistant bacterial strains. It then comparatively describes the antimicrobial properties of CSAs with a focus on the CSA-13 family. More recently developed members of this family such as CSA-90 and CSA-131 may have a particular advantage in an orthopedic setting as they possess secondary pro-osteogenic properties. In this context, we consider several new preclinical studies that demonstrate the utility of CSAs in orthopedic models. Emerging evidence suggests that CSAs are effective against antibiotic-resistant Staphylococcus aureus strains and can prevent the formation of biofilms. There remains considerable scope for developing CSA-based treatments, either as coatings for orthopedic implants or as local or systemic antibiotics to prevent bone infection.
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http://dx.doi.org/10.1002/jor.24615DOI Listing
September 2020

Draft Opioid-Prescribing Guidelines for Uncomplicated Normal Spontaneous Vaginal Birth.

Obstet Gynecol 2019 01;133(1):81-90

University of Illinois at Chicago, Chicago, Illinois; Novartis Oncology, East Hanover, New Jersey; U.S. Department of Health and Human Services, Washington, DC; and Premier, Inc, Charlotte, North Carolina.

Women who experience an uncomplicated vaginal delivery have acute intrapartum pain and variable pain in the immediate postpartum period. Although the Centers for Disease Control and Prevention (CDC) has urged clinicians to improve opioid-prescribing behavior, there are no published clinical practice guidelines for prescribing opioids during labor and delivery and at discharge for patients with uncomplicated normal spontaneous vaginal delivery. To address the knowledge gap regarding guidelines for pain management in this population, we used the national Premiere Health Care Database for deliveries of uncomplicated vaginal births from January 1, 2014, to December 31, 2016, to determine the prevalence of opioid administration. Among the 49,133 women who met inclusion criteria, 78.2% were administered opioids during hospitalization and 29.8% were administered opioids on the day of discharge. Descriptive statistics were generated to document the characteristics of the patients receiving opioids as well as the characteristics of hospitals administering opioids during inpatient labor and delivery and on discharge. Patient-level variables included age group, marital status, race, ethnicity, payer type, and length of stay. Hospital-level variables included bed size, geographic region, teaching status, and urbanicity status. These data were then presented in an electronic Delphi survey to 14 participants. The survey participants were obstetrician-gynecologists identified by the American College of Obstetricians and Gynecologists as being thought leaders in the obstetrics field and who had also demonstrated an active interest in the opioid epidemic and its effect on women's health. After the panelists viewed the opioid administration data, they were presented with an adapted version of the CDC's guidelines for opioid prescribing for chronic pain management. The eight adapted guidelines were constructed to be more relevant and appropriate for the inpatient normal spontaneous vaginal delivery population. After three rounds of the surveying process, seven of the eight adapted guidelines were endorsed by the survey participants. These seven draft consensus guidelines could now be used as a starting point to develop more broadly endorsed and studied guidelines for appropriately managing pain control for women with uncomplicated spontaneous vaginal birth.
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http://dx.doi.org/10.1097/AOG.0000000000002996DOI Listing
January 2019

RHEGAL: Resistive heating gas enclosure loadframe for neutron scattering.

Rev Sci Instrum 2018 Sep;89(9):092901

Spallation Neutron Source, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, USA.

neutron scattering is a powerful tool to reveal materials atomic structural response such as phase transformation, lattice straining, and texture under external stimuli. The advent of a high flux neutron source such as the Spallation Neutron Source (SNS) allows fast measurement in even non-equilibrium conditions, i.e., phase transformation in steels. However, the commercial fast heating apparatus such as commercial physical simulation equipment is not designed for neutron scattering, which limits its application to materials research by using neutrons. Here we present a resistive heating gas enclosure loadframe (RHEGAL) for non-equilibrium phase transformation studies by using neutron scattering, which takes the advantage of high flux neutron sources like SNS. RHEGAL enables fast resistive heating of metal samples to 1200 °C at a rate up to 60 °C/s in an inert atmosphere. It provides both horizontal and vertical positions for scattering optimization. The mechanical loading capability also allows high temperature tension above the oxidation temperature limit. The optimized translucent neutron scattering window by silicon allows both reflection and transmission measurements, making this equipment applicable for neutron diffraction, small angle scattering, and imaging. To demonstrate the fast heating capability, the phase transformations of an example of advanced high strength steel heated at 3 °C/s and 30 °C/s were measured with the VULCAN engineering diffractometer, and the different phase transformation kinetics by neutron diffraction were presented.
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http://dx.doi.org/10.1063/1.5033566DOI Listing
September 2018

A high temperature gas flow environment for neutron total scattering studies of complex materials.

Rev Sci Instrum 2018 Sep;89(9):092906

Neutron Scattering Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831-6454, USA.

We present the design and capabilities of a high temperature gas flow environment for neutron diffraction and pair distribution function studies available at the Nanoscale Ordered Materials Diffractometer instrument at the Spallation Neutron Source. Design considerations for successful total scattering studies are discussed, and guidance for planning experiments, preparing samples, and correcting and reducing data is defined. The new capabilities are demonstrated with an decomposition study of a battery electrode material under inert gas flow and an carbonation/decarbonation experiment under reactive gas flow. This capability will aid in identifying and quantifying the atomistic configurations of chemically reactive species and their influence on underlying crystal structures. Furthermore, studies of reaction kinetics and growth pathways in a wide variety of functional materials can be performed across a range of length scales spanning the atomic to the nanoscale.
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http://dx.doi.org/10.1063/1.5033464DOI Listing
September 2018

CSA-90 Promotes Bone Formation and Mitigates Methicillin-resistant Staphylococcus aureus Infection in a Rat Open Fracture Model.

Clin Orthop Relat Res 2018 06;476(6):1311-1323

R. Mills, T. L. Cheng, K. Mikulec, L. Peacock, D. G. Little, A. Schindeler, Orthopedic Research & Biotechnology Unit, The Children's Hospital at Westmead, Sydney, Australia T. L. Cheng, D. Isaacs, D. G. Little, A. Schindeler, Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Sydney, NSW, Australia D. Isaacs, Department of Infectious Diseases & Microbiology, Children's Hospital at Westmead, Westmead, NSW, Australia C. Genberg, N8 Medical, Dublin, OH, USA P. B. Savage, Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT, USA.

Background: Infection of open fractures remains a significant cause of morbidity and mortality to patients worldwide. Early administration of prophylactic antibiotics is known to improve outcomes; however, increasing concern regarding antimicrobial resistance makes finding new compounds for use in such cases a pressing area for further research. CSA-90, a synthetic peptidomimetic compound, has previously demonstrated promising antimicrobial action against Staphylococcus aureus in rat open fractures. However, its efficacy against antibiotic-resistant microorganisms, its potential as a therapeutic agent in addition to its prophylactic effects, and its proosteogenic properties all require further investigation.

Questions/purposes: (1) Does prophylactic treatment with CSA-90 reduce infection rates in a rat open fracture model inoculated with S aureus, methicillin-resistant S aureus (MRSA), and methicillin-resistant Staphylococcus epidermidis (MRSE) as measured by survival, radiographic union, and deep tissue swab cultures? (2) Does CSA-90 reduce infection rates when administered later in the management of an open fracture as measured by survival, radiographic union, and deep tissue swab cultures? (3) Does CSA-90 demonstrate a synergistic proosteogenic effect with bone morphogenetic protein 2 (BMP-2) in a noninfected rat ectopic bone formation assay as assessed by micro-CT bone volume measurement? (4) Can CSA-90 elute and retain its antimicrobial efficacy in vitro when delivered using clinically relevant agents measured using a Kirby-Bauer disc diffusion assay?

Methods: All in vivo studies were approved by the local animal ethics committee. In the open fracture studies, 12-week-old male Wistar rats underwent open midshaft femoral fractures stabilized with a 1.1-mm Kirschner wire and 10 µg BMP-2 ± 500 µg CSA-90 was applied to the fracture site using a collagen sponge along with 1 x 10 colony-forming units of bacteria (S aureus/MRSA/MRSE; n = 10 per group). In the delayed treatment study, débridement and treatment with 500 µg CSA-90 were performed at Day 1 and Day 5 after injury and bacterial insult (S aureus). All animals were reviewed daily for signs of local infection and/or sepsis. An independent, blinded veterinarian reviewed twice-weekly radiographs, and rats showing osteolysis and/or declining overall health were culled at his instruction. The primary outcome of both fracture studies was fracture infection, incorporating survival, radiographic union, and deep tissue swab cultures. For the ectopic bone formation assay, 0 to 10 µg BMP-2 and 0 to 500 µg CSA-90 were delivered on a collagen sponge into bilateral quadriceps muscle pouches of 8-week-old rats (n = 10 per group). Micro-CT quantification of bone volume and descriptive histologic analysis were performed for all in vivo studies. Modified Kirby-Bauer disc diffusion assays were used to quantify antimicrobial activity in vitro using four different delivery methods, including bone cement.

Results: Infection was observed in none of the MRSA inoculated open fractures treated with CSA-90 with 10 of 10 deep tissue swab cultures negative at the time of cull. Median survival was 43 days (range, 11-43 days) in the treated group versus 11 days (range, 8-11 days) in the untreated MRSA inoculated group (p < 0.001). However, delayed débridement and treatment of open fractures with CSA-90 at either Day 1 or Day 5 did not prevent infection, resulting in early culls by Day 21 with positive swab cultures (10 of 10 for each time point). Maximal ectopic bone formation was achieved with 500 μg CSA-90 and 10 μg BMP-2 (mean volume, 9.58 mm; SD, 7.83), creating larger bone nodules than formed with 250 μg CSA-90 and 10 μg BMP-2 (mean volume, 1.7 mm; SD, 1.07; p < 0.001). Disc diffusion assays showed that CSA-90 could successfully elute from four potential delivery agents including calcium sulphate (mean zone of inhibition, 11.35 mm; SD, 0.957) and bone cement (mean, 4.67 mm; SD, 0.516).

Conclusions: CSA-90 shows antimicrobial action against antibiotic-resistant Staphylococcal strains in vitro and in an in vivo model of open fracture infection.

Clinical Relevance: The antimicrobial properties of CSA-90 combined with further evidence of its proosteogenic potential make it a promising compound to develop further for orthopaedic applications.
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http://dx.doi.org/10.1097/01.blo.0000533624.79802.e1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6263573PMC
June 2018

Preclinical models for orthopedic research and bone tissue engineering.

J Orthop Res 2018 03 19;36(3):832-840. Epub 2017 Dec 19.

Orthopedic Research and Biotechnology Unit, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, Sydney, New South Wales, 2145, Australia.

In this review, we broadly define and discuss the preclinical rodent models that are used for orthopedics and bone tissue engineering. These range from implantation models typically used for biocompatibility testing and high-throughput drug screening, through to fracture and critical defect models used to model bone healing and severe orthopedic injuries. As well as highlighting the key methods papers describing these techniques, we provide additional commentary based on our substantive practical experience with animal surgery and in vivo experimental design. This review also briefly touches upon the descriptive and functional outcome measures and power calculations that are necessary for an informative study. Obtaining informative and relevant research outcomes can be very dependent on the model used, and we hope this evaluation of common models will serve as a primer for new researchers looking to undertake preclinical bone studies. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:832-840, 2018.
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http://dx.doi.org/10.1002/jor.23824DOI Listing
March 2018

A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape.

Nat Commun 2016 11 23;7:13357. Epub 2016 Nov 23.

Department of Kinesiology, Laval University, Québec, Québec, Canada G1V 0A6.

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.
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http://dx.doi.org/10.1038/ncomms13357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5114527PMC
November 2016

Correlation and comparison of syndesmosis dimension on CT and MRI.

Foot (Edinb) 2016 Aug 23;28:36-41. Epub 2016 Jun 23.

Adult Foot and Ankle Reconstruction Unit, Guy's & St Thomas' Hospital NHS Foundation Trust, Great Maze Pond, London Bridge, SE9 2RT, London, United Kingdom.

Introduction: Various methods using CT scan have been described to diagnose distal tibiofibular syndesmotic injuries. However, CT scan does not take into account the amount of cartilage within the distal tibiofibular joint and could therefore lead to false positive results. We present the first study correlating the findings of the distal tibiofibular syndesmosis on CT and MRI scans.

Methods: CT and MRI scan of consecutive patients over a period of 18 months, and of a time lapsed less than 12 months between the two imaging modalities, were reviewed. Measurements of the distal tibiofibular syndesmosis were taken according to a previously published study at the level of the distal tibial physeal scar.

Results: Twenty-six ankles from 25 patients were included in this study for analysis. Significant difference between CT and MRI assessments in the overall distal tibiofibular dimensions and in the posterior distal tibiofibular distance for those ankles with evidence of osteoarthritis was found. Interclass correlation coefficients suggest that such methodology was reproducible and reliable.

Conclusion: When the widening found on a CT scan is minor or the diagnosis is equivocal, a contralateral comparative CT or an ipsilateral MRI scan is recommended to prevent misdiagnosis.

Level Of Evidence: Level IV.
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http://dx.doi.org/10.1016/j.foot.2016.06.001DOI Listing
August 2016

Targeted expression of HvHMA2 increases the mineral content of the inner endosperm in barley.

Plant Biotechnol J 2016 Sep 29. Epub 2016 Sep 29.

Department of Molecular Biology and Genetics, Research Centre Flakkebjerg, Aarhus University, Denmark.

Cereals are a major source of dietary energy and protein but are nutritionally poor in micronutrients. Zinc (Zn) biofortification of staple crops has been proposed as a promising strategy to combat the global challenge of human Zn-deficiency. The aim of this study was to improve the Zn content in the edible part of the barley (Hordeum vulgare L.) grain by enhancing Zn translocation into the developing seeds. We demonstrate that the barley plasma membrane P-type ATPase Zn transporter, HvHMA2 is an efficient candidate for mineral biofortification of crops. Following a cisgenic approach to produce transgenic homozygous barley line over-expressing HvHMA2 in the transfer cells of the grain, resulted in a doubling of a wide range of nutrients including Zn, iron (Fe), and magnesium (Mg) in the inner endosperm. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/pbi.12642DOI Listing
September 2016

Detection of light and vibration modulates bioluminescence intensity in the glowworm, Arachnocampa flava.

J Comp Physiol A Neuroethol Sens Neural Behav Physiol 2016 Apr 20;202(4):313-27. Epub 2016 Feb 20.

School Biological Sciences, The University of Queensland, Brisbane, QLD, 4072, Australia.

Glowworms are larval fungus gnats that emit light from a specialised abdominal light organ. The light attracts small arthropod prey to their web-like silk snares. Larvae glow throughout the night and can modulate their bioluminescence in response to sensory input. To better understand light output regulation and its ecological significance, we examined the larvae's reaction to light exposure, vibration and sound. Exposure to a 5-min light pulse in the laboratory causes larvae to exponentially decrease their light output over 5-10 min until they completely switch off. They gradually return to pre-exposure levels but do not show a rebound. Larvae are most sensitive to ultraviolet light, then blue, green and red. Vibration of the larval snares results in a several-fold increase in bioluminescence over 20-30 s, followed by an exponential return to pre-exposure levels over 15-30 min. Under some conditions, larvae can respond to vibration by initiating bioluminescence when they are not glowing; however, the response is reduced compared to when they are glowing. We propose that inhibitory and excitatory mechanisms combine to modulate bioluminescence intensity by regulating biochemical reactions or gating the access of air to the light organ.
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http://dx.doi.org/10.1007/s00359-016-1077-0DOI Listing
April 2016

Onset of Cooperative Dynamics in an Equilibrium Glass-Forming Metallic Liquid.

J Phys Chem B 2016 Feb 3;120(6):1142-8. Epub 2016 Feb 3.

Department of Nuclear, Plasma and Radiological Engineering, University of Illinois at Urbana-Champaign , Urbana, Illinois 61801, United States.

Onset of cooperative dynamics has been observed in many molecular liquids, colloids, and granular materials in the metastable regime on approaching their respective glass or jamming transition points, and is considered to play a significant role in the emergence of the slow dynamics. However, the nature of such dynamical cooperativity remains elusive in multicomponent metallic liquids characterized by complex many-body interactions and high mixing entropy. Herein, we report evidence of onset of cooperative dynamics in an equilibrium glass-forming metallic liquid (LM601: Zr51Cu36Ni4Al9). This is revealed by deviation of the mean effective diffusion coefficient from its high-temperature Arrhenius behavior below TA ≈ 1300 K, i.e., a crossover from uncorrelated dynamics above TA to landscape-influenced correlated dynamics below TA. Furthermore, the onset/crossover temperature TA in such a multicomponent bulk metallic glass-forming liquid is observed at approximately twice of its calorimetric glass transition temperature (Tg ≈ 697 K) and in its stable liquid phase, unlike many molecular liquids.
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http://dx.doi.org/10.1021/acs.jpcb.5b11452DOI Listing
February 2016

Opioid Medication Practices Observed in Chronic Pain Patients Presenting for All-Causes to Emergency Departments: Prevalence and Impact on Health Care Outcomes.

J Manag Care Spec Pharm 2015 Oct;21(10):925-36

Indegene TTM, 222 Chastain Meadows Ct., Ste. 300, Kennesaw, GA 30144.

Background: Chronic pain is a significant health problem that affects an estimated 100 million American adults (aged ≥ 18 years). Chronic pain affects more individuals than heart disease, stroke, diabetes, and cancer combined. Chronic pain sufferers cost up to $635 billion annually in medical treatment and lost productivity. Opioids are commonly used to treat chronic pain, but their metabolic interactions with concurrently prescribed medications for concomitant disease burdens can affect potency and efficacy of pain therapy. Additionally, misuse of short-acting opioids (SAOs) for chronic pain versus breakthrough pain can create gaps in pain relief. These potentially suboptimal prescribing practices may contribute to the high economic impact associated with chronic pain. 

Objective: To examine the prevalence of suboptimal opioid therapy and the associated health care costs resulting from these prescribing practices in real-world patients presenting for all-causes to the emergency department (ED). 

Methods: This retrospective observational database cohort analysis used the linked Premier-Optum database and included patients with ED visits from 2006 to 2010 having ≥ 60 days supply of opioids in the 75 days prior to the visit. Suboptimal prescribing practices were identified as patients with (a) drug-drug exposures (DDEs), defined as cytochrome P-450 (CYP-450)-metabolized opioids prescribed concurrently with CYP-450 inhibitors or inducers and/or (b) monotherapy with SAOs. Comorbid conditions and principal diagnoses were documented. Readmission rates to the ED and hospital within 72 hours as well as ≤ 30, ≤ 45, ≤ 60, and ≤ 90 days were computed. Total costs for health care were calculated, and reimbursement rates were normalized using 2011 Medicare severity diagnosis-related group (MS-DRG) and CPT-4 information. Nonparametric bootstrapping to adjust for patient comorbidities was applied to cost data.

Results: Of the 9,214 patients identified with chronic pain, potentially suboptimal medication practices prior to the index ED visit were found for 8,539 (92.6%) patients. These appeared to be corrected in 345 (4.0%) patients before leaving the ED. Of 675 (7.3%) patients without prior DDE or exclusive use of SAOs, 345 (51.1%) patients were discharged with one of these. Of the 8,352 patients who left the ED with DDE or exclusive use of SAOs, 1,525 (18.3%) left with a DDE without exclusive SAO use; 4,812 (57.6%) left with both DDE and exclusive SAO use; and 2,015 (24.1%) left with only exclusive SAO use. Only 862 (9.3%) patients from the entire cohort left the ED without DDE or exclusive SAO use. Patients identified with suboptimal opioid use were aged 50 ± 13.5 years and were predominantly female (64.0%). Hypertension (44.0%), fluid and electrolyte disorders (32.7%), chronic pulmonary disease (22.8%), depression (19.6%), diabetes without chronic complications (16.2%), and drug abuse (15.6%) were the most prevalent comorbid conditions identified. The most prevalent principal diagnoses involved symptoms and signs of ill-defined conditions (36.5%), injury and poisoning (18.2%), and diseases of the musculoskeletal system (13.2%). The majority of revisits to the ED and hospital admissions occurred within 72 hours (73.6%) of the index visit and within 30 days (70%), respectively. When adjusted total costs were compared for all patients whose opioid use included DDE versus those without, a significantly greater cost (P  less than  0.05) was observed at every time period except ≤ 72 hours. Respective mean increases in costs were $581, $689, $773, and $1,275 at 30, 45, 60, and 90 days. Exclusive SAO use with or without DDE resulted in a significant increase (P  less than  0.05) in mean costs at all times: $214 at 72 hours; $836 at 30 days; $1,023 at 45 days; $1,022 at 60 days; and $1,536 at 90 days. 

Conclusions: This study identified potentially suboptimal opioid prescribing practices in a real-world population presenting for all-causes to the ED. The observed rate of ED revisits and inpatient admissions in these patients was associated with increased health care costs. These findings suggest that the ED has the future potential to serve as an ideal setting to identify and correct such practices, thereby improving patient care and reducing resource use and beneficiary costs.
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http://dx.doi.org/10.18553/jmcp.2015.21.10.925DOI Listing
October 2015

Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation.

Nat Genet 2015 11 21;47(11):1282-1293. Epub 2015 Sep 21.

Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore.

We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10(-11) to 5.0 × 10(-21)). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10(-6)). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.
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http://dx.doi.org/10.1038/ng.3405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4719169PMC
November 2015

New genetic loci link adipose and insulin biology to body fat distribution.

Nature 2015 Feb;518(7538):187-196

Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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http://dx.doi.org/10.1038/nature14132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338562PMC
February 2015

The South Asian genome.

PLoS One 2014 12;9(8):e102645. Epub 2014 Aug 12.

BGI-Shenzhen, Shenzhen, China.

The genetic sequence variation of people from the Indian subcontinent who comprise one-quarter of the world's population, is not well described. We carried out whole genome sequencing of 168 South Asians, along with whole-exome sequencing of 147 South Asians to provide deeper characterisation of coding regions. We identify 12,962,155 autosomal sequence variants, including 2,946,861 new SNPs and 312,738 novel indels. This catalogue of SNPs and indels amongst South Asians provides the first comprehensive map of genetic variation in this major human population, and reveals evidence for selective pressures on genes involved in skin biology, metabolism, infection and immunity. Our results will accelerate the search for the genetic variants underlying susceptibility to disorders such as type-2 diabetes and cardiovascular disease which are highly prevalent amongst South Asians.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0102645PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4130493PMC
April 2015

Approach to engineer tomato by expression of AtHMA4 to enhance Zn in the aerial parts.

J Plant Physiol 2014 Sep 12;171(15):1413-22. Epub 2014 Jun 12.

University of Warsaw, Faculty of Biology, Institute of Experimental Plant Biology and Biotechnology, Miecznikowa Str. 1, 02-096 Warszawa, Poland. Electronic address:

The aim of this work was to assess the potential for using AtHMA4 to engineer enhanced efficiency of Zn translocation to shoots, and to increase the Zn concentration in aerial tissues of tomato. AtHMA4, a P1B-ATPase, encodes a Zn export protein known to be involved in the control of Zn root-to-shoot translocation. In this work, 35S::AtHMA4 was expressed in tomato (Lycopersicon esculentum var. Beta). Wild-type and transgenic plants were tested for Zn and Cd tolerance; Zn, Fe and Cd accumulation patterns, and for the expression of endogenous Zn/Fe-homeostasis genes. At 10μM Zn exposure, a higher Zn concentration was observed in leaves of AtHMA4-expressing lines compared to wild-type, which is promising in terms of Zn biofortification. AtHMA4 also transports Cd and at 0.25μM Cd the transgenic plants showed similar levels of this element in leaves to wild-type but lower levels in roots, therefore indicating a reduction of Cd uptake due to AtHMA4 expression. Expression of this transgene AtHMA4 also resulted in distinct changes in Fe accumulation in Zn-exposed plants, and Fe/Zn-accumulation in Cd-exposed plants, even though Fe is not a substrate for AtHMA4. Analysis of the transcript abundance of key Zn/Fe-homeostasis genes showed that the pattern was distinct for transgenic and wild-type plants. The reduction of Fe accumulation observed in AtHMA4-transformants was accompanied by up-regulation of Fe-deficiency marker genes (LeFER, LeFRO1, LeIRT1), whereas down-regulation was detected in plants with the status of Fe-sufficiency. Furthermore, results strongly suggest the importance of the up-regulation of LeCHLN in the roots of AtHMA4-expressing plants for efficient translocation of Zn to the shoots. Thus, the modifications of Zn/Fe/Cd translocation to aerial plant parts due to AtHMA4 expression are closely related to the alteration of the endogenous Zn-Fe-Cd cross-homeostasis network of tomato.
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http://dx.doi.org/10.1016/j.jplph.2014.04.017DOI Listing
September 2014

Improving care of patients with metastatic spinal cord compression.

Br J Nurs 2014 Feb 27-Mar 12;23(4):S14-8

Clinical Oncology Consultant, Weston Park Hospital, Specialist Cancer Services, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield.

Metastatic spinal cord compression is a feature of advanced cancer and the incidence is likely to increase alongside improved survival rates. Patients with spinal cord compression have complex physical, psychological and social care needs. This article describes a multidisciplinary project aimed at improving the care provided to newly diagnosed patients who were admitted to a regional cancer centre for radiotherapy. The project used a range of approaches to measure care, develop and implement interventions, and evaluate outcomes. Aspects of care reviewed in the project included mobilisation, medications including steroids and thrombo-prophylaxis, bowel management, patient priorities and concerns, discharge planning and early detection.
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http://dx.doi.org/10.12968/bjon.2014.23.Sup2.S14DOI Listing
May 2014

Expression of HvHMA2 in tobacco modifies Zn-Fe-Cd homeostasis.

J Plant Physiol 2013 Sep 9;170(13):1176-86. Epub 2013 May 9.

Institute of Experimental Plant Biology and Biotechnology, Faculty of Biology, University of Warsaw, Miecznikowa Street 1, 02-096 Warszawa, Poland.

HvHMA2 is a plasma membrane P1B-ATPase from barley that functions in Zn/Cd root-to-shoot transport. To assess the usefulness of HvHMA2 for modifying the metal content in aerial plant parts, it was expressed in tobacco under the CaMV35S promoter. Transformation with HvHMA2 did not produce one unique pattern of Zn and Cd accumulation; instead it depended on external metal supply. Thus Zn and Cd root-to-shoot translocation was facilitated, but not at all applied Zn/Cd concentrations. Metal uptake was restricted in HvHMA2-transformed plants and the level in the shoot was not enhanced. It was shown that HvHMA2 localizes to the plasma membrane of tobacco cells, and overloads the apoplast with Zn, which could explain the overall decrease in metal uptake observed. Despite the lower levels in the shoot, HvHMA2 transformants showed increased Zn sensitivity. Moreover, introduction of HvHMA2 into tobacco interfered with Fe metabolism and Fe accumulation was modified in HvHMA2-transformants in a Zn- and Cd-concentration dependent manner. The results indicate that ectopic expression of the export protein HvHMA2 in tobacco interferes with tobacco metal Zn-Cd-Fe cross-homeostasis, inducing internal mechanisms regulating metal uptake and tolerance.
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http://dx.doi.org/10.1016/j.jplph.2013.03.018DOI Listing
September 2013

Comparison of costs between transradial and transfemoral percutaneous coronary intervention: a cohort analysis from the Premier research database.

Am Heart J 2013 Mar 15;165(3):303-9.e2. Epub 2012 Nov 15.

St. Lukes's Mid America Heart Institute, St Luke's Hospital, Kansas City, MO, USA.

Background: Transradial intervention (TRI) for percutaneous coronary intervention (PCI) is associated with shorter length of stay, fewer bleeding complications, and higher patient satisfaction. Less is known about the economic implications of TRI in contemporary practice.

Methods: This is a retrospective inpatient cohort analysis using medical data from the Premier research database (Premier Inc, Charlotte, NC), which contains approximately one-fifth of all acute care hospitalizations in the US annually. The database was queried to identify patients undergoing PCI from 2004 to 2009. Patients with TRI were identified by center-level charge codes for radial-specific devices and matched one-to-many with patients undergoing transfemoral intervention (TFI). Adjusted total hospitalization costs were compared between patients undergoing TRI and TFI. Patients were additionally classified by periprocedural risk of bleeding as low (<1%), moderate (1%-3%), and high (>3%).

Results: There were 609 TRI cases matched with 60,900 TFI cases. Total adjusted costs for TRI were $11,736 ± $6,748 vs $12,288 ± $23,418 for TFI, a difference of $553 favoring TRI (95% CI $45-$1,060, P = .033). Day-of-procedure costs were similar, at $17 higher for TRI compared with TFI (95% CI -$318 to $353, P = .37); however, costs from the following day until discharge were significantly lower for TRI (-$571, 95 % CI -$912 to $229, P = .001). Postprocedure costs were lower for patients with TRI vs patients with TFI at moderate (-$478, 95% CI -$887 to $69, P = .022) and high (-$917, 95% CI -$1,814 to $19, P = .045) risk of bleeding.

Conclusions: In a nationwide administrative hospital database, transradial compared with transfemoral PCI access was associated with lower average direct hospital costs and shorter length of hospital stay. Postprocedure costs associated with TRI were also lower in patients at greater bleeding risk.
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http://dx.doi.org/10.1016/j.ahj.2012.10.004DOI Listing
March 2013

Barley HvHMA1 is a heavy metal pump involved in mobilizing organellar Zn and Cu and plays a role in metal loading into grains.

PLoS One 2012 14;7(11):e49027. Epub 2012 Nov 14.

Centre for Membrane Pumps in Cells and Disease (PUMPKIN), Danish National Research Foundation, Frederiksberg, Denmark.

Heavy metal transporters belonging to the P(1B)-ATPase subfamily of P-type ATPases are key players in cellular heavy metal homeostasis. Heavy metal transporters belonging to the P(1B)-ATPase subfamily of P-type ATPases are key players in cellular heavy metal homeostasis. In this study we investigated the properties of HvHMA1, which is a barley orthologue of Arabidopsis thaliana AtHMA1 localized to the chloroplast envelope. HvHMA1 was localized to the periphery of chloroplast of leaves and in intracellular compartments of grain aleurone cells. HvHMA1 expression was significantly higher in grains compared to leaves. In leaves, HvHMA1 expression was moderately induced by Zn deficiency, but reduced by toxic levels of Zn, Cu and Cd. Isolated barley chloroplasts exported Zn and Cu when supplied with Mg-ATP and this transport was inhibited by the AtHMA1 inhibitor thapsigargin. Down-regulation of HvHMA1 by RNA interference did not have an effect on foliar Zn and Cu contents but resulted in a significant increase in grain Zn and Cu content. Heterologous expression of HvHMA1 in heavy metal-sensitive yeast strains increased their sensitivity to Zn, but also to Cu, Co, Cd, Ca, Mn, and Fe. Based on these results, we suggest that HvHMA1 is a broad-specificity exporter of metals from chloroplasts and serve as a scavenging mechanism for mobilizing plastid Zn and Cu when cells become deficient in these elements. In grains, HvHMA1 might be involved in mobilizing Zn and Cu from the aleurone cells during grain filling and germination.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0049027PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498361PMC
May 2013

HvHMA2, a P(1B)-ATPase from barley, is highly conserved among cereals and functions in Zn and Cd transport.

PLoS One 2012 3;7(8):e42640. Epub 2012 Aug 3.

Centre for Biological Sciences, University of Southampton, Highfield Campus, Southampton, United Kingdom.

Manipulation of crops to improve their nutritional value (biofortification) and optimisation of plants for removal of toxic metals from contaminated soils (phytoremediation) are major goals. Identification of membrane transporters with roles in zinc and cadmium transport would be useful for both aspects. The P(1B)-ATPases play important roles in heavy metal allocation and detoxification in Arabidopsis and it is now important to elucidate their roles in monocots. We identified nine P(1B)-ATPases in barley and this study focuses on the functional characterization of HvHMA2, providing evidence for its role in heavy metal transport. HvHMA2 was cloned using information from EST analysis and 5' RACE. It possesses the conserved aspartate that is phosphorylated during the reaction cycle of P-type pumps and has motifs and key residues characteristic of P(1B)-ATPases, falling into the P(1B-2) subclass. Homologous sequences occur in three major sub-families of the Poaceae (Gramineae). Heterologous expression in Saccharomyces cerevisiae demonstrates that HvHMA2 functions as a Zn and Cd pump. Mutagenesis studies show that proposed cation coordination sites of the P(1B-2) pumps are crucial for the metal responses conferred by HvHMA2 in yeast. HvHMA2 expression suppresses the Zn-deficient phenotype of the Arabidopsis hma2hma4 mutant indicating that HvHMA2 functions as a Zn pump in planta and could play a role in root to shoot Zn transport. When expressed in Arabidopsis, HvHMA2 localises predominantly to the plasma membrane.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0042640PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3411818PMC
January 2013

Functional significance of AtHMA4 C-terminal domain in planta.

PLoS One 2010 Oct 20;5(10):e13388. Epub 2010 Oct 20.

School of Biological Sciences, University of Southampton, Southampton, Hampshire, United Kingdom.

Background: Enhancing the upward translocation of heavy metals such as Zn from root to shoot through genetic engineering has potential for biofortification and phytoremediation. This study examined the contribution of the heavy metal-transporting ATPase, AtHMA4, to the shoot ionomic profile of soil-grown plants, and investigated the importance of the C-terminal domain in the functioning of this transporter.

Principal Findings: The Arabidopsis hma2 hma4 mutant has a stunted phenotype and a distinctive ionomic profile, with low shoot levels of Zn, Cd, Co, K and Rb, and high shoot Cu. Expression of AtHMA4 (AtHMA4-FL) under the CaMV-35S promoter partially rescued the stunted phenotype of hma2 hma4; rosette diameter returned to wild-type levels in the majority of lines and bolts were also produced, although the average bolt height was not restored completely. AtHMA4-FL expression rescued Co, K, Rb and Cu to wild-type levels, and partially returned Cd and Zn levels (83% and 28% of wild type respectively). In contrast, expression of AtHMA4-trunc (without the C-terminal region) in hma2 hma4 only partially restored the rosette diameter in two of five lines and bolt production was not rescued. There was no significant effect on the shoot ionomic profile, apart from Cd, which was increased to 41% of wild-type levels. When the AtHMA4 C-terminal domain (AtHMA4-C-term) was expressed in hma2 hma4 it had no marked effect. When expressed in yeast, AtHMA4-C-term and AtHMA4-trunc conferred greater Cd and Zn tolerance than AtHMA4-FL.

Conclusion: The ionome of the hma2 hma4 mutant differs markedly from wt plants. The functional relevance of domains of AtHMA4 in planta can be explored by complementing this mutant. AtHMA4-FL is more effective in restoring shoot metal accumulation in this mutant than a C-terminally truncated version of the pump, indicating that the C-terminal domain is important in the functioning of AtHMA4 in planta.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0013388PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2958113PMC
October 2010

A combined zinc/cadmium sensor and zinc/cadmium export regulator in a heavy metal pump.

J Biol Chem 2010 Oct 22;285(41):31243-52. Epub 2010 Jul 22.

Department of Plant Biology and Biotechnology, Centre for Membrane Pumps in Cells and Disease, PUMPKIN, Danish National Research Foundation, University of Copenhagen, Thorvaldsensvej 40, DK-1871 Frederiksberg C, Denmark.

Heavy metal pumps (P1B-ATPases) are important for cellular heavy metal homeostasis. AtHMA4, an Arabidopsis thaliana heavy metal pump of importance for plant Zn(2+) nutrition, has an extended C-terminal domain containing 13 cysteine pairs and a terminal stretch of 11 histidines. Using a novel size-exclusion chromatography, inductively coupled plasma mass spectrometry approach we report that the C-terminal domain of AtHMA4 is a high affinity Zn(2+) and Cd(2+) chelator with capacity to bind 10 Zn(2+) ions per C terminus. When AtHMA4 is expressed in a Zn(2+)-sensitive zrc1 cot1 yeast strain, sequential removal of the histidine stretch and the cysteine pairs confers a gradual increase in Zn(2+) and Cd(2+) tolerance and lowered Zn(2+) and Cd(2+) content of transformed yeast cells. We conclude that the C-terminal domain of AtHMA4 serves a dual role as Zn(2+) and Cd(2+) chelator (sensor) and as a regulator of the efficiency of Zn(2+) and Cd(2+) export. The identification of a post-translational handle on Zn(2+) and Cd(2+) transport efficiency opens new perspectives for regulation of Zn(2+) nutrition and tolerance in eukaryotes.
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http://dx.doi.org/10.1074/jbc.M110.111260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2951198PMC
October 2010

Expression of the P(₁B) -type ATPase AtHMA4 in tobacco modifies Zn and Cd root to shoot partitioning and metal tolerance.

Plant Biotechnol J 2011 Jan;9(1):64-74

University of Warsaw, Institute of Experimental Plant Biology, Warszawa, Poland.

Genetic modification of Zn/Cd accumulation in roots and shoots for biofortification or phytoremediation is a focus of this manuscript. We expressed AtHMA4 (a P(₁B) ATPase involved in Zn and Cd transport), AtHMA4-trunc (lacking the C-terminal region) and AtHMA4-C terminus (the C-terminal region alone) in tobacco under the CaMV 35S constitutive promoter and examined accumulation and tolerance to both metals. Expression of AtHMA4 enhanced Zn translocation to the shoots only at 10 μM Zn but not at 0.5, 100 and 200 μM Zn. AtHMA4-trunc did not show this effect and instead reduced Zn translocation to the shoot. AtHMA4-expressing plants showed a decrease in cadmium uptake when exposed to 0.25 and 5 μM Cd; this was also observed with AtHMA4-trunc-expressing lines, although to a lesser extent. Expression of AtHMA4-C-terminus containing potential metal binding sites increased cadmium and zinc concentrations in roots and shoots up to fourfold. We have demonstrated that both AtHMA4 and AtHMA4 C-terminus could be candidate genes/sequences for engineering modifications of zinc and cadmium root/shoot partitioning. However, the phenotype of transformants depended on the external metal concentration, thus it might be difficult to engineer a plant displaying the desired metal-related phenotype when grown under varying conditions of metal supply.
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http://dx.doi.org/10.1111/j.1467-7652.2010.00531.xDOI Listing
January 2011
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